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Design and Synthesis of 3‐Carbamoylbenzoic Acid Derivatives as Inhibitors of Human Apurinic/Apyrimidinic Endonuclease 1 (APE1)
Author(s) -
Aiello Francesca,
Shabaik Yumna,
Esqueda Adrian,
Sanchez Tino W.,
Grande Fedora,
Garofalo Antonio,
Neamati Nouri
Publication year - 2012
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201200334
Subject(s) - ap site , endonuclease , base excision repair , dna (apurinic or apyrimidinic site) lyase , ap endonuclease , biochemistry , function (biology) , enzyme , cytotoxicity , chemistry , in vitro , biology , dna repair , dna , microbiology and biotechnology
Apurinic/apyrimidinic (AP) endonuclease 1 (APE1) is a multifaceted protein with an essential role in the base excision repair (BER) pathway. Its implication in tumor development, progression, and resistance has been confirmed in multiple cancers, making it a viable target for intensive investigation. In this work, we designed and synthesized different classes of small‐molecule inhibitors of the catalytic endonuclease function of APE1 that contain a 3‐carbamoylbenzoic acid scaffold. Further structural modifications were made with the aim of increasing the activity and cytotoxicity of these inhibitors. Several of our compounds were shown to inhibit the catalytic endonuclease function of APE1 with potencies in the low‐micromolar range in vitro, and therefore represent novel classes of APE1 inhibitors worthy of further development.